Project Summary Alcoholic liver disease (ALD) is a result of chronic intake of excessive alcohol. In the United States, 40% of liver-related death is associated with alcohol consumption. The spectrum of ALD ranges from alcoholic fatty liver, alcoholic hepatitis (AH), alcoholic cirrhosis and hepatocellular carcinoma (HCC). Although alcoholic fatty liver is considered a benign liver disease, the mortality of AH is high, as 40 % of severe AH patients die within 6 months. Treatment of AH is still largely dependent on corticosteroid and pentoxifylline, with no significant progress in the past 40 years. Since the translocation of intestine-derived lipopolysaccharide (LPS) is observed in ALD, it is conceivable that Toll-like receptor (TLR) signaling contributes to the development of ALD. For a decade, we have investigated the molecular mechanisms of TLR-mediated ALD and examined the therapeutic agents targeting TLRs. TLR2, TLR4, and TLR9 signaling promotes the development of ALD. Our previous study found the protective role of TLR7 signaling in liver fibrosis, which is in contrast to other TLRs that promote liver disease. To date, the molecular mechanisms of the protective effect of TLR7 signaling and natural ligands for TLR7 in liver disease are poorly understood. In addition, the functional role of TLR7 signaling in AH is unknown. The central hypothesis of this proposal is that TLR7 signaling is a negative regulator of liver inflammation, which prevents exacerbation of AH, and activation of TLR7 signaling could be an effective therapy for AH. In the proposed study, Aim 1 will characterize the molecular mechanisms of the TLR7-mediated liver protection in AH. Aim 2 will seek the endogenous ligands for TLR7 and examine the role of exosomes as vehicles for TLR7 endogenous ligands. Aim 3 will examine a novel TLR7 ligand that is highly safer than existing TLR7 ligands as a potential therapeutic approach for AH. If the proposed study is successfully achieved, our results will provide significant insights into the new mechanisms of TLR7 signaling and endogenous ligands for TLR7 in AH, and the new therapeutic approach for AH.